EP0044575B1 - Zwischenprodukte in der Herstellung von 2-substituierten 19-nor-Steroiden - Google Patents

Zwischenprodukte in der Herstellung von 2-substituierten 19-nor-Steroiden Download PDF

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Publication number
EP0044575B1
EP0044575B1 EP81200353A EP81200353A EP0044575B1 EP 0044575 B1 EP0044575 B1 EP 0044575B1 EP 81200353 A EP81200353 A EP 81200353A EP 81200353 A EP81200353 A EP 81200353A EP 0044575 B1 EP0044575 B1 EP 0044575B1
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European Patent Office
Prior art keywords
formula
mixture
isomers
agent
carbon atoms
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EP81200353A
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English (en)
French (fr)
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EP0044575A1 (de
Inventor
Lucien Nedelec
Vesperto Torelli
Robert Fournex
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Sanofi Aventis France
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Roussel Uclaf SA
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Priority to AT81200353T priority Critical patent/ATE6783T1/de
Priority to DE7979400873T priority patent/DE2962843D1/de
Publication of EP0044575A1 publication Critical patent/EP0044575A1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/006—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa

Definitions

  • the present invention relates to new intermediates of structured 19-nor steroid and substituted in position 2 as well as their preparation process.
  • French patents 1,476,572 and Swiss patents 473,106 were known to contain 19-nor products comprising an acetyl radical or a 1-hydroxy ethyl radical in the 17 ⁇ position. However, the products of the prior art do not include any substitution in position 2.
  • the subject of the invention is the products of formula Ii: in the form of 20R or 20S isomers or of their mixture, formula in which R 1 and R 2 identical or different represent a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms or an alkenyl or alkynyl radical containing from 2 to 6 carbon atoms, it being understood that only one of the substituents R 1 and R 2 can represent a hydrogen atom, or else R 1 and R 2 together form a cycloalkyl radical containing 3 to 8 carbon atoms; R 3 represents an alkyl radical containing from 2 to 4 carbon atoms; OD representing an ether group.
  • R 1 or R 2 represents an alkyl radical, it is preferably a methyl or ethyl radical.
  • R 1 or R 2 represents an alkenyl radical, it is preferably an allyl radical.
  • R 1 or R 2 represents an alkynyl radical, it is preferably the 2-propynyl radical.
  • R 1 or R 2 together form a cycloalkyl radical, it is preferably the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.
  • the invention particularly relates to the products of formula li as defined above, for which R 3 represents an ethyl radical as well as those for which R 1 and R 2 each represent a methyl radical.
  • a more specific subject of the invention is (2'R, S, 20R, S) 2,2-dimethyl 13-ethyl 20- / 2 '- (tetrahydropyrannyl) oxy / 18,19-dinor pregn-4- then 3-one.
  • the subject of the invention is also a process for preparing the products of formula Ii, characterized in that a compound of formula II is condensed, by reaction of WITTIG: in which K and K ′ represent a ketone group blocked in the form of a ketal and R 3 represents an alkyl radical containing from 2 to 4 carbon atoms, with a triphenyl ethyl phosphonium halide of formula III: in which Hal represents a halogen atom, in the presence of a strong base, to obtain a compound of formula IV: in the form of a mixture of cis and trans isomers, which are separated, if desired, into each of the isomers, then subject either each of the isomers of formula IV, or their mixture, to the action of an agent d hydroboration, then to that of an oxidizing agent in an alkaline medium and finally to that of a decetalization agent and to that of a cyclization agent, to obtain a compound of formula V: in the form of 20R
  • the gem-dimethylation reaction is advantageously carried out in an aprotic solvent such as, for example, tetrahydrofuran.
  • R 3 represents an alkyl radical containing from 2 to 4 carbon atoms
  • R ' 4 represents a hydrogen atom, a hydroxyl radical, an acyloxy radical containing from 1 to 18 carbon atoms or a radical: in which M represents a hydrogen atom, a sodium or potassium atom, and either R 1 and R 2 , which are identical or different, represent a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms , or an alkenyl or alkynyl radical containing 2 to 6 carbon atoms, it being understood that only one of the substituents R 1 and R 2 can represent a hydrogen atom, or else R 1 and R 2 together form a cycloalkyl radical containing 3 to 8 carbon atoms.
  • the compounds of formula I have interesting pharmacological properties; they are in particular antagonists of aldosterone and increase the diuresis hydrosodée with conservation of organic potassium, while being devoid of side effects. It has been observed in particular that at the doses where the products exhibit an interesting anti-aldosterone activity, these do not show anti-androgenic activity nor antiestrogenic activity. They can therefore be used to combat high blood pressure and heart failure.
  • the salification of the phosphorus derivative is carried out with sodium or potassium hydroxide.
  • the products of formula II, used as starting materials for the process of the invention are generally known products and which can be prepared according to the processes described in French patent 1,490,590 and in Danish patent 136,115.
  • Stage A bis (1,2-ethanediyl) cyclic acetal of 13-ethyl 18,19-dinor 4,5-seco pregn 17 (20) -en 3,5-dione (mixture of Z and E isomers)
  • triphenyl ethyl phosphonium bromide 51.2 g of triphenyl ethyl phosphonium bromide are introduced into 136 cm 3 of dimethyl sulfoxide containing 16.8 g of potassium terbutylate. Then added 27.2 g of cyclic bis (1,2-ethanediylacetal) of 13-ethyl 18,19-dinor 4,5 seco androstane 17-one. The mixture is heated with stirring and under a stream of nitrogen at 50 ° C. for 65 hours and the reaction mixture is poured into 1.5 l of water. Extracted with ether. The organic phase is washed with water, dried and concentrated under reduced pressure to small volume. The triphenylphosphonium oxide is filtered off and the filtrate is concentrated to dryness.
  • the organic phase is washed twice with 3N sodium hydroxide and 100 cm 3 of 3N sodium hydroxide are added thereto.
  • the two phases are emulsified by stirring and 50 cm 3 of 33% perhydrol are added slowly at room temperature. Stirring is continued for 45 minutes and then the aqueous phase is decanted and extracted with ethyl acetate.
  • the combined organic phases are washed with a 10% sodium thiosulfate solution, dried and concentrated to dryness under reduced pressure.
  • 100 cm 3 of ethanol and 50 cm 3 of approximately 5N hydrochloric acid are added to the residue and the solution obtained is heated at reflux for 50 minutes. Then diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated under reduced pressure.
  • Stage C 13-ethyl (2'RS, 20RS) 20- / 2 '- (tetrahydropyrannyl) oxy / 18,19-dinor pregn 4-en 3-one
  • Stage D (2'RS, 20RS) 2,2-dimethyl 13-ethyl 20- / 2 '- (tetrahydropyrannyl) oxy / 18,19-dinor pregn 4-en 3- one
  • the 7.1 g of the product obtained in Stage D are dissolved in a solution containing 70 cm 3 of ethanol and 14 cm 3 of 2N hydrochloric acid. The mixture is heated to reflux for 1 hour then diluted with water and extracted with methylene chloride.
  • the dry extract (6.9 g) is dissolved in 200 cm 3 of acetone.
  • the mixture is cooled to 0 ° -5 ° C. and 5 cm 3 of HEILBRON-JONES reagent are added over 15 minutes.
  • the mixture is stirred for a further 15 minutes at 0 ° -5 ° C. and then the excess reagent is destroyed by adding methanol, diluted with water and extracted with methylene chloride. 5.9 g of a product are obtained which is purified by chromatography on silica eluting with a mixture of cyclohexane-ethyl acetate (85-15). 2.6 g of the desired product are obtained, melting at 179 ° C. after recrystallization from a methylene chloride-isopropyl ether mixture.
  • Example 2 3.4 g of the product obtained in Example 2 are dissolved in 68 cm 3 of methanol. The solution is heated to reflux with nitrogen bubbling for 15 minutes, then 840 mg of potassium acid carbonate and 8.4 cm 3 of water are added. Maintained at reflux under nitrogen bubbling for 30 minutes, cooled and added 1 cm 3 of acetic acid. It is concentrated under reduced pressure, diluted with water and extracted with methylene chloride. The organic phase is washed with water and dried. It is evaporated to dryness. 3.06 g of product are obtained which is purified by chromatography on silica (eluent: benzene-ethyl acetate 8-2). 3 g of the desired product are obtained, melting at 138 ° C. after recrystallization from aqueous ethanol.
  • Tablets containing 50 mg of product of Example 3 were prepared, as active ingredient.
  • the animals are fasted seventeen hours before diuresis, the physiological saline is then replaced by 5% glucose water.
  • the product is administered orally one hour before caging.
  • the animals receive a hydrosaline overload intraperitoneally at a rate of 5 ml per rat, of physiological saline at 9% and on the other hand, 1 ⁇ g / kg of aldosterone monoacetate in alcoholic solution at 2.5%, subcutaneously.
  • the rats are then placed in pairs in a diuresis cage, without food or drink, for four hours.
  • a forced urination is carried out by pressing on the bladder and measuring the volume of the urine collected.
  • the volume of urine is brought to 50 cm 3 .
  • the urinary sodium and potassium are measured by flame photometry with an autoanalyzer.
  • results obtained are expressed as a percentage inhibition of the activity of 1 ⁇ g / kg of aldosterone monoacetate injected subcutaneously on the log of the ratio: sodium concentration / potassium concentration, according to the KAGAWA method. Endocrinology 1960, 67 p. 125-132.
  • product A at a dose of 2 mg / kg, orally, exhibits a very marked antialdosterone activity; the percentage of inhibition is at this dose of the order of 60%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Claims (3)

1. Die Produkte der Formel Ii :
Figure imgb0029
in Form der Isomeren 20R oder 20S oder in Form von deren Gemisch, wobei in der Formel R1 und R2, die gleich oder verschieden sein können, ein Wasserstoffatom, einen Alkylrest mit 1 bis 4 Kohlenstoffatomen oder einen Alkenyl- oder Alkinylrest mit 2 bis 6 Kohlenstoffatomen bedeuten, wobei lediglich einer der Substituenten R1 und R2 ein Wasserstoffatom bedeuten kann, oder R1 und R2 gemeinsam einen Cycloalkylrest mit 3 bis 8 Kohlenstoffatomen bilden ; R3 einen Alkylrest mit 2 bis 4 Kohlenstoffatomen bedeutet ; und OD eine Ethergruppe darstellt.
2. (2'R,S,20R,S)-2,2-Dimethyl-13-ethyl-20-[2'-(tetrahydropyranyl)-oxy]-18,19-dinor-pregn-4-en-3-on.
3. Verfahren zur Herstellung der Produkte gemäß Anspruch 1, dadurch gekennzeichnet, daß man durch Wittig-Reaktion eine Verbindung der Formel II :
Figure imgb0030
worin K und K' eine in Form des Ketals blockierte Ketongruppe darstellen und R3 einen Alkylrest mit 2 bis 4 Kohlenstoffatomen bedeutet, mit einem Triphenylethylphosphonium-halogenid der Formel III :
Figure imgb0031
worin Hal ein Halogenatom bedeutet, in Gegenwart einer starken Base kondensiert, um eine Verbindung der Formel IV :
Figure imgb0032
in Form eines Gemisches der cis- und trans-Isomeren zu erhalten, das man gewünschtenfalls in ein jedes der Isomeren auftrennt, danach
entweder ein jedes der Isomeren der Formel IV oder ihr Gemisch der Einwirkung eines Hydroborierungsmittels, dann derjenigen eines Oxidationsmittels in alkalischem Milieu und schließlich derjenigen eines Diketalisierungsmittels und derjenigen eines Cyclisierungsmittels unterzieht, um eine Verbindung der Formel V :
Figure imgb0033
in Form der Isomeren 20R oder 20S oder in Form von deren Gemisch zu erhalten,
entweder ein jedes der Isomeren der Formel V oder deren Gemisch der Einwirkung eines Blockierungsmittels für die Alkoholfunktion in Form eines leicht spaltbaren Ethers unterzieht, um eine Verbindung der Formel VI :
Figure imgb0034
in Form der Isomeren 20R oder 20S oder in Form von deren Gemisch zu erhalten, worin OD eine Ethergruppe bedeutet, und entweder
ein jedes der Isomeren der Formel VI oder deren Gemisch der Einwirkung eines Alkyl-, Alkenyl- oder Alkinylhalogenids in Gegenwart eines basischen Mittels bei niedriger Temperatur unterzieht, um eine Verbindung der Formel VII :
Figure imgb0035
worin R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen, in Form des Isomeren 20R oder 20S oder in Form von deren Gemisch zu erhalten.
EP81200353A 1978-12-13 1979-11-14 Zwischenprodukte in der Herstellung von 2-substituierten 19-nor-Steroiden Expired EP0044575B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AT81200353T ATE6783T1 (de) 1978-12-13 1979-11-14 Zwischenprodukte in der herstellung von 2substituierten 19-nor-steroiden.
DE7979400873T DE2962843D1 (en) 1978-12-13 1979-11-14 Substituted-19-nor-pregn-4-ene-3,20-dione derivatives, process for their preparation and pharmaceutical compositions containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7835046A FR2444047A1 (fr) 1978-12-13 1978-12-13 Nouveaux derives 2,2-dimethyl 19-nor steroides, leur procede de preparation et leur application comme medicaments
FR7835046 1978-12-13

Related Parent Applications (1)

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EP79400873.0 Division 1979-11-14

Publications (2)

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EP0044575A1 EP0044575A1 (de) 1982-01-27
EP0044575B1 true EP0044575B1 (de) 1984-03-21

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EP79400873A Expired EP0012641B1 (de) 1978-12-13 1979-11-14 Substituierte-19-nor-pregn-4-en-3,20-dion-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
EP81200353A Expired EP0044575B1 (de) 1978-12-13 1979-11-14 Zwischenprodukte in der Herstellung von 2-substituierten 19-nor-Steroiden

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EP79400873A Expired EP0012641B1 (de) 1978-12-13 1979-11-14 Substituierte-19-nor-pregn-4-en-3,20-dion-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen

Country Status (14)

Country Link
US (1) US4263290A (de)
EP (2) EP0012641B1 (de)
JP (1) JPS5585598A (de)
AU (1) AU527582B2 (de)
CA (1) CA1146531A (de)
DK (1) DK527379A (de)
ES (1) ES8102149A1 (de)
FI (1) FI70027C (de)
FR (1) FR2444047A1 (de)
HU (1) HU180931B (de)
IE (1) IE49235B1 (de)
PT (1) PT70575A (de)
SU (1) SU1178325A3 (de)
ZA (1) ZA796194B (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012523A1 (en) * 1992-11-30 1994-06-09 Mallinckrodt Medical, Inc. Steroid-21-phosphate complex of technetium-99m
US20030083231A1 (en) * 1998-11-24 2003-05-01 Ahlem Clarence N. Blood cell deficiency treatment method
FR2917975B1 (fr) * 2007-06-26 2009-10-16 Ceva Sante Animale Sa Compositions et traitement de l'insuffisance cardiaque chez les animaux mammiferes non humains
US20090270356A1 (en) * 2008-04-28 2009-10-29 Ceva Sante Animale Sa Compositions and treatments of heart failure in non-human mammal animals
EP2632471B1 (de) 2010-10-27 2019-05-01 Dignity Health Trimegeston (tmg) zur behandlung von frühgeburten

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1138460A (en) * 1965-06-01 1969-01-01 Merck & Co Inc Steroid compounds
FR1476572A (fr) * 1965-09-13 1967-04-14 Gonènes synthétiques et leur procédé de préparation
FR2322606A1 (fr) * 1975-09-02 1977-04-01 Roussel Uclaf Nouveaux 2,2-dimethyl steroides, leur procede de preparation et leur application comme medicament
FR2364655A1 (fr) * 1976-09-17 1978-04-14 Roussel Uclaf Nouveaux 2,2-dimethyl 19-nor steroides, leur procede de preparation et leur application comme medicament

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EP0012641A3 (en) 1980-09-17
ES486791A0 (es) 1980-12-16
AU5376279A (en) 1980-07-10
IE49235B1 (en) 1985-09-04
DK527379A (da) 1980-06-14
US4263290A (en) 1981-04-21
FI70027C (fi) 1986-09-12
EP0012641B1 (de) 1982-05-12
IE792420L (en) 1980-06-13
PT70575A (fr) 1980-01-01
FI70027B (fi) 1986-01-31
FR2444047A1 (fr) 1980-07-11
EP0044575A1 (de) 1982-01-27
ZA796194B (en) 1980-11-26
FI793847A (fi) 1980-06-14
JPS6337796B2 (de) 1988-07-27
SU1178325A3 (ru) 1985-09-07
HU180931B (en) 1983-05-30
AU527582B2 (en) 1983-03-10
EP0012641A2 (de) 1980-06-25
JPS5585598A (en) 1980-06-27
CA1146531A (fr) 1983-05-17
ES8102149A1 (es) 1980-12-16
FR2444047B1 (de) 1982-05-28

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